A mentored award to allow the principal investigator to further develop his skills in epidemiology and running clinical trials with the ultimate career goal of reaching independence as an investigator in the epidemiology, prevention, and treatment of malaria. Background: Malaria is Africa's leading cause of mortality in children under 5 years of age. Per WHO recommendations, trimethoprim-sulfamethoxazole (TS) prophylaxis is used throughout Africa in all HIV- infected and exposed (uninfected children born to infected mothers) children to prevent opportunistic infections but is also very effective in preventing malaria. There are concerns, however, that the use of TS prophylaxis will also prevent children in malaria-endemic areas from developing antimalarial immunity, and thus, increase their risk of contracting malaria following cessation of TS prophylaxis. Primary Hypothesis: Prolonged TS prophylaxis will result in increased or rebound incidence of malaria following cessation of TS. Research Design and Methods: We have recently begun a project in rural Uganda to study the interactions between HIV and malaria. We have enrolled 200 HIV-uninfected children born to infected mothers (HIV- exposed). Per WHO guidelines, we place all HIV-exposed children on TS prophylaxis at 6 weeks of age. This cohort will undergo 2 randomizations so that 100 of the children (Group 2A) will stop TS after breastfeeding (~9 months of age), 50 children (Group 2B) will discontinue TS at 2 years of age, and 50 children (Group 2C) will discontinue prophylaxis at 4 years of age. All children will be followed until 5 years of age. Using this established cohort I will compare the incidence of malaria between those recently discontinued from TS and those off TS for more than a year during 2 separate time periods (2-3 years of age and 4-5 years of age) to assess the risk of rebound malaria following TS prophylaxis. We will also use previously validated antibody tests to assess if children develop antimalarial immunity while on TS prophylaxis and investigate whether these tests can be used to predict rebound malaria following prophylaxis cessation. RELEVANCE: Despite the widespread use of TS prophylaxis in Africa and interests in antifolate malaria chemoprevention, rebound incidence of malaria has never been studied following TS prophylaxis. This study will help clarify the full effect of TS prophylaxis in HIV-exposed children and the implications of mass chemoprophylaxis.